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DOI: 10.1055/a-1384-0818
Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials
Gentherapie für erbliche Netzhauterkrankungen: Übersicht zu aktuellen klinischen Studien![](https://www.thieme-connect.de/media/klimo/202103/lookinside/thumbnails/10-1055-a-1384-0818_kl2308-1.jpg)
Abstract
Within the last decade, continuous advances in molecular biological techniques have made it possible to develop causative therapies for inherited retinal disorders (IRDs). Some of the most promising options are gene-specific approaches using adeno-associated virus-based vectors to express a healthy copy of the disease-causing gene in affected cells of a patient. This concept of gene supplementation therapy is already advocated for the treatment of retinal dystrophy in RPE65-linked Leberʼs congenital amaurosis (LCA) patients. While the concept of gene supplementation therapy can be applied to treat autosomal recessive and X-linked forms of IRD, it is not sufficient for autosomal dominant IRDs, where the pathogenic gene product needs to be removed. Therefore, for autosomal dominant IRDs, alternative approaches that utilize CRISPR/Cas9 or antisense oligonucleotides to edit or deplete the mutant allele or gene product are needed. In recent years, research retinal gene therapy has intensified and promising approaches for various forms of IRD are currently in preclinical and clinical development. This review article provides an overview of current clinical trials for the treatment of IRDs.
Zusammenfassung
Stetige Fortschritte in molekularbiologischen und genetischen Techniken ermöglichten es innerhalb der letzten Jahre, die Entwicklung ursächlicher Therapien für erbliche Netzhauterkrankungen (IRD) voranzubringen. Zu den vielversprechendsten Ansätzen gehört die Gensupplementierungstherapie, bei der mittels Adeno-assoziierten Viren (AAV) eine gesunde Kopie des krankheitsverursachenden Gens in die betroffenen Zellen eines Patienten eingeschleust wird. Dieses Therapiekonzept ist bereits bei RPE65-assoziierten Netzhautdystrophien, wie beispielsweise einer Form der Leberʼschen kongenitalen Amaurose (LCA2) als Therapie zugelassen. Während das Konzept der Gensupplementierungstherapie zur Behandlung autosomal-rezessiver und X-chromosomaler Formen von IRD angewendet werden kann, muss bei autosomal-dominanten IRDs, zusätzlich zur Gensupplementation, das pathogene Genprodukt entfernt werden. Daher sind für autosomal-dominante IRDs alternative Ansätze erforderlich, die CRISPR/Cas9- oder Antisense-Oligonukleotide verwenden, um das mutierte Allel oder Genprodukt gezielt zu eliminieren. In den letzten Jahren wurden die Forschungsaktivitäten auf dem Gebiet der retinalen Gentherapie intensiviert und etliche, vielversprechende Ansätze für verschiedene Formen der IRD befinden sich derzeit in der präklinischen und klinischen Entwicklung. Mit diesem Übersichtsartikel möchten wir einen Überblick über aktuelle Studien zur Behandlung von IRDs bieten und einen Ausblick auf zukünftige Entwicklungen geben.
Key words
AAV - adeno-associated virus - achromatopsia - inherited retinal dystrophies - Leberʼs congenital amaurosis - retinitis pigmentosaSchlüsselwörter
AAV - Adeno-assoziierte Viren - Achromatopsie - erbliche Netzhauterkrankungen - Retinitis pigmentosa - Leberʼsche kongenitale AmaurosePublikationsverlauf
Eingereicht: 28. Oktober 2020
Angenommen: 03. Februar 2021
Artikel online veröffentlicht:
30. März 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
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References
- 1 Cremers FPM, Boon CJF, Bujakowska K. et al. Special Issue Introduction: Inherited Retinal Disease: Novel Candidate Genes, Genotype-Phenotype Correlations, and Inheritance Models. Genes (Basel) 2018; 9: 215 doi:10.3390/genes9040215
- 2 Awwad S, Mohamed Ahmed AHA, Sharma G. et al. Principles of pharmacology in the eye. Br J Pharmacol 2017; 174: 4205-4223 doi:10.1111/bph.14024
- 3 Kiser PD, Palczewski K. Retinoids and Retinal Diseases. Annu Rev Vis Sci 2016; 2: 197-234 doi:10.1146/annurev-vision-111815-114407
- 4 Hussain RM, Gregori NZ, Ciulla TA. et al. Pharmacotherapy of retinal disease with visual cycle modulators. Expert Opin Pharmacother 2018; 19: 471-481 doi:10.1080/14656566.2018.1448060
- 5 Pardue MT, Allen RS. Neuroprotective strategies for retinal disease. Prog Retin Eye Res 2018; 65: 50-76 doi:10.1016/j.preteyeres.2018.02.002
- 6 Jin ZB, Gao ML, Deng WL. et al. Stemming retinal regeneration with pluripotent stem cells. Prog Retin Eye Res 2019; 69: 38-56 doi:10.1016/j.preteyeres.2018.11.003
- 7 Mills JO, Jalil A, Stanga PE. Electronic retinal implants and artificial vision: journey and present. Eye (Lond) 2017; 31: 1383-1398 doi:10.1038/eye.2017.65
- 8 Auricchio A, Smith AJ, Ali RR. The Future Looks Brighter After 25 Years of Retinal Gene Therapy. Hum Gene Ther 2017; 28: 982-987 doi:10.1089/hum.2017.164
- 9 Boutin S, Monteilhet V, Veron P. et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther 2010; 21: 704-712 doi:10.1089/hum.2009.182
- 10 Rabinowitz J, Chan YK, Samulski RJ. Adeno-associated Virus (AAV) versus Immune Response. Viruses 2019; 11: 102 doi:10.3390/v11020102
- 11 Samulski RJ, Berns KI, Tan M. et al. Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc Natl Acad Sci U S A 1982; 79: 2077-2081 doi:10.1073/pnas.79.6.2077
- 12 Penaud-Budloo M, Francois A, Clement N. et al. Pharmacology of Recombinant Adeno-associated Virus Production. Mol Ther Methods Clin Dev 2018; 8: 166-180 doi:10.1016/j.omtm.2018.01.002
- 13 Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res 2014; 43: 108-128 doi:10.1016/j.preteyeres.2014.08.001
- 14 Keeler AM, Flotte TR. Recombinant Adeno-Associated Virus Gene Therapy in Light of Luxturna (and Zolgensma and Glybera): Where Are We, and How Did We Get Here?. Annu Rev Virol 2019; 6: 601-621 doi:10.1146/annurev-virology-092818-015530
- 15 Cideciyan AV, Jacobson SG, Beltran WA. et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 2013; 110: E517-E525 doi:10.1073/pnas.1218933110
- 16 Russell S, Bennett J, Wellman JA. et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 2017; 390: 849-860 doi:10.1016/S0140-6736(17)31868-8
- 17 Michalakis S, Schön C, Becirovic E. et al. Gene therapy for achromatopsia. J Gene Med 2017; 19 doi:10.1002/jgm.2944
- 18 Fischer MD, Michalakis S, Wilhelm B. et al. Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol 2020; 138: 643-651 doi:10.1001/jamaophthalmol.2020.1032
- 19 De Silva SR, Arno G, Robson AG. et al. The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies. Prog Retin Eye Res 2020; DOI: 10.1016/j.preteyeres.2020.100898.
- 20 Xue K, Jolly JK, Barnard AR. et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med 2018; 24: 1507-1512 doi:10.1038/s41591-018-0185-5
- 21 Fischer MD, Ochakovski GA, Beier B. et al. Changes in Retinal Sensitivity after Gene Therapy in Choroideremia. Retina 2020; 40: 160-168 doi:10.1097/IAE.0000000000002360
- 22 den Hollander AI. Roepman R, Koenekoop RK. et al. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 2008; 27: 391-419 doi:10.1016/j.preteyeres.2008.05.003
- 23 Bouzia Z, Georgiou M, Hull S. et al. GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies. Am J Ophthalmol 2020; 210: 59-70 doi:10.1016/j.ajo.2019.10.019
- 24 Feldhaus B, Weisschuh N, Nasser F. et al. CEP290 Mutation Spectrum and Delineation of the Associated Phenotype in a Large German Cohort: A Monocentric Study. Am J Ophthalmol 2020; 211: 142-150 doi:10.1016/j.ajo.2019.11.012
- 25 Pasadhika S, Fishman GA, Stone EM. et al. Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis. Invest Ophthalmol Vis Sci 2010; 51: 2608-2614 doi:10.1167/iovs.09-3734
- 26 Dulla K, Aguila M, Lane A. et al. Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models. Mol Ther Nucleic Acids 2018; 12: 730-740 doi:10.1016/j.omtn.2018.07.010
- 27 Cideciyan AV, Jacobson SG, Drack AV. et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med 2019; 25: 225-228 doi:10.1038/s41591-018-0295-0
- 28 Ruan GX, Barry E, Yu D. et al. CRISPR/Cas9-Mediated Genome Editing as a Therapeutic Approach for Leber Congenital Amaurosis 10. Mol Ther 2017; 25: 331-341 doi:10.1016/j.ymthe.2016.12.006
- 29 Maeder ML, Stefanidakis M, Wilson CJ. et al. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nat Med 2019; 25: 229-233 doi:10.1038/s41591-018-0327-9
- 30 Priglinger C, Klopstock T, Rudolph G. et al. [Leberʼs Hereditary Optic Neuropathy]. Klin Monbl Augenheilkd 2019; 236: 1271-1282 doi:10.1055/a-0972-1552
- 31 Yu-Wai-Man P, Newman NJ, Carelli V. et al. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med 2020; 12: eaaz7423 doi:10.1126/scitranslmed.aaz7423
- 32 Newman NJ, Yu-Wai-Man P, Carelli V. et al. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset. Ophthalmology 2021; DOI: 10.1016/j.ophtha.2020.12.012.
- 33 Verbakel SK, van Huet RAC, Boon CJF. et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res 2018; 66: 157-186 doi:10.1016/j.preteyeres.2018.03.005
- 34 Ghazi NG, Abboud EB, Nowilaty SR. et al. Treatment of retinitis pigmentosa due to MERTK mutations by ocular subretinal injection of adeno-associated virus gene vector: results of a phase I trial. Hum Genet 2016; 135: 327-343 doi:10.1007/s00439-016-1637-y
- 35 Cehajic Kapetanovic J, McClements ME, Martinez-Fernandez de la Camara C. et al. Molecular Strategies for RPGR Gene Therapy. Genes (Basel) 2019; 10: 674 doi:10.3390/genes10090674
- 36 Talib M, van Schooneveld MJ, Thiadens AA. et al. Clinical and genetic characteristics of male patients with RPGR-associated retinal dystrophies: A Long-Term Follow-up Study. Retina 2019; 39: 1186-1199 doi:10.1097/IAE.0000000000002125
- 37 Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C. et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med 2020; 26: 354-359 doi:10.1038/s41591-020-0763-1
- 38 Cukras C, Wiley HE, Jeffrey BG. et al. Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Mol Ther 2018; 26: 2282-2294 doi:10.1016/j.ymthe.2018.05.025
- 39 Corporation AGT. AGTC Announces Topline Interim Six-Month Data from Phase 1/2 X-Linked Retinoschisis Clinical Study; Termination of Biogen Collaboration. Accessed October 26, 2020 at. https://agtc.com/agtc-announces-topline-interim-six-month-data-from-phase-1-2-x-linked-retinoschisis-clinical-study-termination-of-biogen-collaboration/
- 40 Quazi F, Lenevich S, Molday RS. ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer. Nat Commun 2012; 3: 925 doi:10.1038/ncomms1927
- 41 Parker MA, Choi D, Erker LR. et al. Test-Retest Variability of Functional and Structural Parameters in Patients with Stargardt Disease Participating in the SAR422459 Gene Therapy Trial. Transl Vis Sci Technol 2016; 5: 10 doi:10.1167/tvst.5.5.10
- 42 Trapani I, Auricchio A. Seeing the Light after 25 Years of Retinal Gene Therapy. Trends Mol Med 2018; 24: 669-681 doi:10.1016/j.molmed.2018.06.006
- 43 Ochakovski GA, Bartz-Schmidt KU, Fischer MD. Retinal Gene Therapy: Surgical Vector Delivery in the Translation to Clinical Trials. Front Neurosci 2017; 11: 174 doi:10.3389/fnins.2017.00174
- 44 Reichel FF, Peters T, Wilhelm B. et al. Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients. Invest Ophthalmol Vis Sci 2018; 59: 1910-1915 doi:10.1167/iovs.17-22494
- 45 Bouquet C, Vignal Clermont C, Galy A. et al. Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial. JAMA Ophthalmol 2019; 137: 399-406 doi:10.1001/jamaophthalmol.2018.6902
- 46 Bucher K, Rodriguez-Bocanegra E, Dauletbekov D. et al. Immune responses to retinal gene therapy using adeno-associated viral vectors – Implications for treatment success and safety. Prog Retin Eye Res 2020; DOI: 10.1016/j.preteyeres.2020.100915.
- 47 Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet 2020; 21: 255-272 doi:10.1038/s41576-019-0205-4
- 48 Yin H, Kanasty RL, Eltoukhy AA. et al. Non-viral vectors for gene-based therapy. Nat Rev Genet 2014; 15: 541-555 doi:10.1038/nrg3763
- 49 Oliveira AV, Rosa da Costa AM, Silva GA. Non-viral strategies for ocular gene delivery. Mater Sci Eng C Mater Biol Appl 2017; 77: 1275-1289 doi:10.1016/j.msec.2017.04.068
- 50 Kelley RA, Conley SM, Makkia R. et al. DNA nanoparticles are safe and nontoxic in non-human primate eyes. Int J Nanomedicine 2018; 13: 1361-1379 doi:10.2147/IJN.S157000